Dr Khan on the Evolution of BTK Inhibitors in CLL

"Compared with ibrutinib, the efficacy [of second-generation BTK inhibitors] is [slightly improved]; however, we go more by the safety profile [in clinical decision-making]. When we use second-generation BTK inhibitors, patients have fewer problems [and adverse effects]. "

Cyrus M. Khan, MD, an assistant professor of medicine at the Drexel University School of Medicine and assistant director of the Stem Cell Transplant Program at the Allegheny Health Network Cancer Institute, discussed the evolution of BTK inhibitors in chronic lymphocytic leukemia (CLL), comparing outcomes with first-generation ibrutinib (Imbruvica) with that of next-generation inhibitors.

Ibrutinib was the only first-generation BTK inhibitor FDA approved for patients with relapsed/refractory CLL in 2014 and first-line CLL in 2016. However, as science progressed, more effective second-generation inhibitors were developed.

The primary motivation for developing newer agents stemmed from the safety profile associated with ibrutinib. Ibrutinib was known to cause significant adverse effects (AEs), including atrial fibrillation, atrial flutter, and dangerous ventricular arrhythmias. Other risks associated with the first-generation agent included a long-term hypertension risk and a general bleeding risk. Patients also commonly experienced nuisance AEs such as arthralgia and myalgia.

The goal of these second-generation BTK inhibitors was to inhibit the BTK site more tightly while having fewer off-target effects than ibrutinib. This preclinical hypothesis suggested fewer AEs, which has subsequently been proven clinically.

Although the efficacy of second-generation agents is only slightly improved, they have a better safety profile than ibrutinib, which is the key factor in clinical decision-making, Khan emphasized. When second-generation BTK inhibitors are used, patients experience fewer problems. With reduced risk of complications like atrial flutter, bleeding, arthralgias, and myalgias, patients are better able to continue treatment and maintain the benefit of BTK inhibition in CLL. Khan concluded that patients are likely to receive benefit from BTK inhibitors for a longer duration when second-generation drugs are utilized.